Editas Medicine Inc

NASDAQ:EDIT

Good morning, and welcome to Editas Medicine's Fourth Quarter and Full Year 2023 Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request.I would now like to turn the call over to Cristi Barnett, Corporate Communications and Investor Relations at Editas Medicine.

Thank you, Maria. Good morning, everyone, and welcome to our Fourth Quarter and Full Year 2023 Conference Call. Earlier this morning, we issued a press release providing our financial results and recent corporate updates. A replay of today's call will be available in the Investors section of our website approximately 2 hours after its completion. After our prepared remarks, we will open the call for Q&A.As a reminder, various remarks that we make during this call about the company's future expectations, plans and prospects constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC as updated by our subsequent filings.In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements even if our views change.Now I will turn the call over to our CEO, Gilmore O'Neill.

Thanks, Cristi, and good morning, everyone. Thank you for joining us today on Editas' Fourth Quarter and Full Year 2023 Earnings Call. I am joined today by 4 other members of the Editas executive team, our Chief Medical Officer, Baisong Mei; our Chief Financial Officer, Erick Lucera; our Chief Scientific Officer, Linda Burkly; and our Chief Commercial and Strategy Officer, Caren Deardorf.We are pleased with Editas' momentum and progress in the fourth quarter and all of 2023. In early 2023, we shared our vision and the 3 pillars of our strategy to position Editas as a leader in in-vivo programmable gene editing and hemoglobinopathies. The first of these pillars, to drive Reni-cel, formerly known as EDIT-301, toward BLA and commercialization. The second, to strengthen, reorganize and focus our discovery organization to build an in vivo editing pipeline. And the third, to increase business development activities with a particular focus on monetizing our very strong IP.So how did we do last year? Well, we achieved a lot. First, we accelerated the clinical development of Reni-cel, exceeding our enrollment goal of 20 patients and sharing clinical updates from our RUBY and EdiTHAL studies in June and in December of 2023. And those accumulating data have strengthened our belief that Reni-cel is a competitive potential medicine with a differentiated profile characterized by correction of anemia into normal physiologic ranges of hemoglobin.Second, we strengthened our in vivo discovery capabilities and organization and hired a new Chief Scientific Officer, Linda Burkly, who brings 3 decades of experience in successfully inventing, developing and moving new human medicines forward. And third, we increased our business development activities and monetized our IP, leveraging our robust IP portfolio. A [ critical ] example was our granting Vertex a nonexclusive license for our Cas9 IP in a focused way to enable the exa-cel launch.Finally, we strengthened our senior leadership team with people who have a proven track record in bringing new medicines through development to approval and commercialization. So how have we executed against these strategies and these objectives?Well, let's start with Reni-cel. First, on enrollment, we have now enrolled 40 sickle cell and 9 beta thalassemia patients in our RUBY and EdiTHAL studies, respectively, and enrollment continues at a good pace. Second, on dosing, we have dosed 18 RUBY patients and 7 EdiTHAL patients, and we have multiple patients scheduled for dosing in the coming months. Patient screening and demand in both studies continue to remain robust.Third, on clinical data, we remain on track to present a substantive clinical data set of sickle cell patients with considerable clinical follow-up in the RUBY study in the middle of 2024, with a further update by year-end 2024. On the regulatory front, we have engaged with the FDA regarding the RUBY sickle cell trial. The FDA agrees that RUBY is a single Phase I/II/III study and has aligned with us on the study design. Our discussions with the FDA will continue as RUBY and EdiTHAL progress and will be enhanced by our RMAT designation for severe sickle cell disease.Baisong will share further details regarding the development of Reni-cel in his remarks as well as recap the RUBY and EdiTHAL takeaways and clinical data that we provided in December and share more information on the adolescent cohort.Now, let's turn to in vivo and our pipeline development, where we strengthened our in vivo discovery capabilities in 2023 and began lead discovery work on in vivo therapeutic targets in hematopoietic stem cells and other tissues. As we announced earlier this year, we aim to establish in vivo preclinical proof of concept for an undisclosed indication this year. Linda and her team are leveraging key capabilities that we have in-house and she look forward to sharing more at a future date.Regarding our hemoglobinopathy focus, after a thorough evaluation of the development landscape, we have decided not to pursue internal development of a milder conditioning regime. We believe stand-alone milder conditioning regimens will be widely available once FDA approved, and therefore, we have determined that our research, clinical development and regulatory investment in hemoglobinopathies can be better deployed for our continued development of in vivo HSC medicines.Turning to business development. In the fourth quarter, we announced a license agreement with Vertex Pharmaceuticals. Editas provided Vertex a non-exclusive license for Editas Medicine's Cas9 gene editing technology for ex vivo gene editing medicines targeting the BCL11A gene in the fields of sickle cell disease and beta thalassemia, including Vertex's CASGEVY. And the upfront and contingent payments pursuant to this agreement extended our cash runway into 2026.This and other agreements, the strength of our patents and the number of companies developing CRISPR/Cas9 medicine reaffirm our confidence that our IP portfolio of foundational U.S. and international patents covering Cas9 used in gene [ medicine ] are a source of meaningful value. So what are our objectives for 2024? For Reni-cel, we will provide a clinical update from the RUBY trial for severe sickle cell disease and the EdiTHAL trial for transfusion-dependent beta thalassemia in mid-2024 and by year-end 2024. We will complete adult cohort enrollment and initiate the adolescent cohort in RUBY, which we've already initiated and continue enrollment in EdiTHAL.For our in vivo pipeline, we will establish in vivo preclinical proof of concept for an undisclosed indication. And for BD, we will leverage our robust IP portfolio and business developments to drive value and complement core gene editing technology capabilities. We are energized by our progress in execution in 2023. With our sharpened strategic focus, our world-class scientists and employees, and our keen drive in execution, we continue to build momentum to progress our strategy to deliver differentiated editing medicines to patients with serious genetic diseases.Now I will turn the call over to Baisong, our Chief Medical Officer.

Thank you, Gilmore. Good morning, everyone. Let's talk about Reni-cel, which is under clinical development for severe sickle cell disease and transfusion-dependent beta thalassemia. As of today, in the RUBY trial for sickle cell disease, we have enrolled 40 patients and dosed 18 patients. We have multiple patients scheduled for dosing in the coming months.We're also pleased to announce that we have initiated adolescent cohort in the RUBY study, which is one of our 2024 objectives. The interest and demand are high and adolescent patients have already started screening.In the EdiTHAL trial for transfusion-dependent beta thalassemia, to-date, we have enrolled 9 patients and dosed 7 patients. As I shared earlier, I continue to visit our RUBY and EdiTHAL clinical trial sites and continuously speak with investigators. I appreciate the enthusiasm and support from the investigators and study size. I'm pleased with the momentum of Reni-cel in patient recruitment, apheresis, editing and dosing in both studies.I'm excited to hear from the investigators that patients dosed with Reni-cel have already seen positive changes in their lives. As Gilmore mentioned, we have aligned with FDA that RUBY clinical trial is now considered a Phase I/II/III trial for BLA filing. We have also aligned with the FDA on the study design and endpoints, and the FDA has agreed to our activation of adolescent cohort. We look forward to future discussions with FDA and continued collaboration.Turning to clinical data. in December 2023, we shared safety and efficacy data from 17 patients; 11 RUBY patients, 6 EdiTHAL patients. Once again, the data confirmed the observation from our prior clinical readouts, including Reni-cel driving early and robust correction of anemia to a normal physiological range of total hemoglobin in sickle cell patients. Reni-cel drove robust and sustained increase in fetal hemoglobin in excess of 40%.All RUBY sickle cell patients have remained free of vaso-occlusive events following Reni-cel treatment. Reni-cel treated sickle cell and beta thalassemia patients have shown successful engraftment, have stopped the red blood cell transfusion. And the safety profile of Reni-cel observed to date is consistent with busulfan myeloablative conditioning and autologous hemopoetic stem cell transplant.In addition, the trajectory of the correction of anemia and expression of fetal hemoglobin is consistent across Reni-cel treated sickle cell disease patients and beta thalassemia patients at the same follow-up time points. These data reinforce our belief that we have a competitive product and the product potentially differentiated from other treatments with rapid correction of anemia.Thanks to the deliberated choice that our discovery group has made early in the program. As we have previously stated, the choice of CRISPR enzyme and the target to edit for increased fetal hemoglobin expression matters. Reni-cel uses our proprietary AsCas12a enzyme to edit the HBG12 promoter. AsCas12a increases efficiency of editing and significantly reduce off-target editing when compared to other CRISPR nucleus, including Cas9.Editing HBG12 promoter in human CD34 positive cells result in greater red blood cell production, normal [ proliferative ] capacity and improved red blood cell health when compared to editing of BCL11A. We look for differentiation in 3 categories of outcome in clinical trials, hematological parameter and organ function and patient reported outcome or quality of life.Based on the clinical data thus far, we believe that sustained normal level of total hemoglobin could be a potential point of differentiation for Reni-cel. As a reminder, a sustained normal total hemoglobin level is an important clinical outcome for patients and the correction of anemia can significantly improve quality of life and ameliorate an organ damage. We look forward to sharing additional updates, including RUBY and EdiTHAL clinical trial data with more patients and longer follow-up period in mid-year and additional data by year-end.Now I'll turn the call over to Erick, our Chief Financial Officer.

Thank you, Baisong, and good morning, everyone. I'm happy to be speaking with you, and I'd like to refer you to our press release issued earlier today for a summary of financial results for the fourth quarter and full year 2023, and I'll take this opportunity to briefly review a few items for the fourth quarter.Our cash, cash equivalents and marketable securities as of December 31 were $427 million, compared to $446 million as of September 30, 2023. We expect our existing cash, cash equivalents and marketable securities, together with the near-term annual license fees and contingent upfront payment payable under our license agreement with Vertex to fund our operating expenses and capital expenditures into 2026.Revenue for the fourth quarter of 2023 was $60 million, which primarily relates to revenue recognized under our license agreement with Vertex, which, as Gilmore referenced earlier on this call, we announced in December of 2023. R&D expenses this quarter increased by $18 million to $70 million from the fourth quarter of 2022. The increase reflects additional sublicense expenses offset by the decrease in R&D spend resulting from our reprioritization and targeted focus on our Reni-cel program.G&A expenses for the fourth quarter of 2023 were $14 million, which decreased from $18 million for the fourth quarter of 2022. The decrease in expense is primarily attributable to reduced patent and legal costs. Overall, Editas remains in a strong financial position, bolstered by our sharpened discovery focus, June capital raise and our recent out-licensing deals. Our cash runway into 2026 provides ample resources to support our continued progress in the RUBY and EdiTHAL clinical trials at Reni-cel, continued commercial manufacturing preparation and the advancement of our discovery and research efforts.With that, I'll hand the call back to Gilmore.

Thank you, Eric. We are very proud of our progress in 2023 and look forward to accelerating the momentum into 2024 as we continue to evolve from a development-stage technology platform company into a commercial stage gene-editing company. We look forward to continue our transformation and sharing our progress with you. As a reminder, our 2024 strategic objectives include; for Reni-cel, we will provide a clinical update on the Reni-cel RUBY trial for severe sickle cell disease and the EdiTHAL trial for transfusion dependent beta thalassemia in mid-2024 and year-end 2024.We will complete adult cohort enrollment, and we already initiated the adolescent cohort in RUBY and will continue enrollment in EdiTHAL. For our in vivo pipeline, we will establish in vivo preclinical proof of concept for an undisclosed indication. And for PD, we will leverage our robust IP portfolio and business development to drive value and complement core gene editing technology capabilities.As always, it must be said that we could not achieve our objectives without the support of our patients, caregivers, investigators, employees, corporate partners and you.Thanks very much for your interest in Editas, and we're happy to answer questions. Thank you.

[Operator Instructions] Our first question comes from Joon Lee with Truist Securities.

Congrats on the quarter, and sorry for my voice. My question is that, could you please elaborate on the hemolysis markers that you're tracking and tell us how they will relate to patient-reported outcomes such as quality of life?

Thanks very much, Joon. I hope that your voice gets better. I'm going to pass that question over to Baisong.

Yes. Thanks for the question, Joon. So for the hemolysis marker, we look into multiple markers for -- indicating for hemolysis, including reticulocytes, LDH, bilirubin, among others. And for the patient report outcome, we use several instruments to measure that clinical outcome and quality of life. And that's related to that, the general [ PRO ] instrument as well as sickle cell specific instrument.

Our next question comes from Samantha Semenkow with Citi.

Can you share just any additional insights into your FDA conversation as you aligned on the RUBY trial, specifically in terms of the number of patients you'll need and the amount of follow-up you'll need to file a potential BLA?

I'm going to have Baisong address that question.

Thank you for the question. So we aligned with the FDA about the RUBY trial and to be a Phase I/II/III trial to support BLA, including endpoint, sample size and study design. And we are still -- we are continuing to have engagement with the FDA about the BLA data package and the follow-up, and -- so we'll have a further discussion with the FDA.

Our next question comes from Brian Cheng with JP Morgan.

Can you just kind of give us a sense of what does the Phase I/II/III destination for RUBY really mean from a timeline perspective? And on the potential differentiation, I think Baisong, you talked about investigators feedback so far. I'm curious if you can also talk about just feedback that you've been hearing from investigators. Are they seeing any potential differentiation this early on?

Thanks very much, Brian. So, I think there were 3 parts to your question. What is the Phase I/II/III and its impact on sort of the BLA path? What was the investigator feedback on differentiation and were they seeing signs or what were the things that they might be seeing in patients at this point?What I'll do is just address the first part and then ask Baisong to follow up on the other 2. So with regard to Phase I/II/III, I think the key point here is that it is a single? We've agreed that there's a single Phase I/II/III study. We have important agreement on what the outcomes are and the size of the study. What that basically means is that we remain on track and are even more confident about being on track to a BLA.I think it's worth calling out that the vertex study was also the study that was used for their BLA application, was designated a Phase I/II/III before or prior to that BLA. So I hope that actually helps from the point of view of our path to BLA. And I think just mentioning Vertex, it's just worth calling out that we sort of have a benchmark based on the BLA filing from last year with regard to the size of the filing that was originally used for that approval. Baisong?

Thanks. So, Brian, on the -- for the differentiation and investigator feedback wise, so we actually have quite a big engagement with investigator and from their own observation of their patients as well as to see the data, they're very pleased to see the correction of anemia. And as a hematologist, that very much appreciate that the level of total hemoglobin be able to correct anemia and they see their patient is less fatigued and they have more energy, and they just -- their direct observation. And then also, they told us that total hemoglobin level, as published also impacted the end organ function. So those are the directions that we're also looking for.

And one other thing I'd just like to quote just with regard to the Phase I/II/III, I think the important thing is that the RUBY study has been -- we've agreed with the FDA, it's converted from a Phase I to a Phase I/II/III, which allows -- because it's a single study, a seamless transition to that study to support BLA. I hope that's helpful.

Yes. Just to add on Gilmore's point, what Gilmore means is also to say we'd be able to use all the patient data from the study to support the BLA.

Our next question comes from Greg Harrison with Bank of America.

Now that there's a gene-editing treatment approved in sickle cell, what are your latest thoughts on how Reni-cel would fit in the space, and what have you learned from the early launch by the competitor?

Thanks very much, Greg. I'm going to ask Caren to address that question.

Yes. Greg, thanks for your question. What we've been hearing from the various stakeholders in this space is a lot of interest and some really good initial momentum. I think we're also hearing that across all of the groups, so your stakeholders, your patients, families, your centers, which are transplant, maybe gene therapy centers, your qualified centers and as well as your payers. There is just a lot of work that needs to happen, and I think you all are picking up on that. But it's starting and it's happening.So, I think it's the balance on saying there is tremendous interest, even from the government in the CMMI pilot that CMS has kicked off. So, the way we see it as it is very encouraging. It's going to take time, and we really believe that the fast follower of Reni-cel is going to be timed very well. Gives us time to be able to continue to collect data that is meaningful, differentiated, to understand where centers may be struggling, where else we can optimize our vein to vein process to deliver a product that's differentiated, not just in efficacy and safety, perhaps, but also in our operational aspects.So we see the market developing in a very robust way. We just think it's going to take a little bit of time. So we're very pleased with initial interest, certainly, the ongoing interest in our clinical studies, and look forward to talking more with you about it.

Our next question comes from Mani Foroohar with Leerink.

You talked a little bit about improvements in vein-to-vein time as an incremental source of differentiation, independent of clinical data. Can you walk through how you guys think of the timing on which we might see that show up in terms of CapEx investments, in terms of clinical execution, et cetera, like where we're going to start seeing data points you could derisk that part of your advantage in the eyes of investors?

Yes, thanks for the question. This is Baisong. Thank you, Mani. We are in the clinical trial stage right. We're already trying to optimize all the process from vein-to-vein, as you mentioned in there too. So we amend our protocol and work with our expert in apheresis for example, and to help the sites in the apheresis cycle and help the site to prepare the patients and provide support. So that's kind of the experience we've gathered now will help for our future commercial launch.I'll pass that to Caren on that.

Yes. And just to add, as we continue to be very engaged in our clinical sites and expanding our outreach to other centers, we have the opportunity to really understand how the process is working, how we make the introduction of a product like Reni-cel as seamless as possible, do the advanced work, fit into their existing processes. But we're always looking at opportunities across just, again, the efficiency, the timing, and we'll certainly be able to talk more as we get closer.

Our next question comes from Terence Flynn with Morgan Stanley.

This is Max Skor on for Terence Flynn. Can you provide an update on the CRISPR/Cas9 appeal case and whether you expect an oral argument in the first half of 2024?

Thanks very much, Max. We have -- the Court of Appeals Federal Circuit has yet to schedule that oral hearing. It should be sometime this year, and once we have that scheduling, we can update you on that.

Our next question comes from Gena Wang with Barclays.

So, if I heard it correctly, Gilmore, you mentioned that the FDA and Baisong -- I think both of you may be mentioned a single study, FDA agree on the single study, also number of patients. I'm not sure if they agree on the duration of the study for RUBY trial. So wondering, if we think about the CRISPR trial, Vertex trial, it's about 45 to 50 patients. Is that aligned with that numbers? And what is the duration that FDA require? And a related question, how many active sites you have now? And what is your goal of total sites for the pivotal study?

Thanks very much, Gena, for your question. Before I -- let me just address a couple of things. From a point of view of the study design, I think, first of all, the benchmark that was set by the BLA with Vertex's approval by the FDA for exa-cel is actually a very good benchmark against which we're operating. And that has certainly informed our discussions with the FDA.We were actually very pleased with the discussion with the FDA, and we believe that it actually really puts us on a track that lines up with the benchmark. And as a result, when we actually talk about having enrolled our 40 patients, how we've initiated the adolescent enrollment and so on, we believe we're actually on a very good track for -- to a BLA.With regard to the number of active sites, I do want to clarify something. We're not talking about a separate study. Essentially, the RUBY study which is ongoing with its sites activated is the Phase I/II/III study that will be used for BLA, and that is the agreement that we have with the agency.

Okay. Sorry, the reason I'm asking, more thinking about in the future commercial perspective, if you have already established the active sites for your clinical trial, then it's very easy to transition this to commercial once drug approved in the future.

Yes, I understand that and appreciate that clarification. And certainly, we agree with that principle. I don't think, Caren, if you want to add to that.

No, no, no. I mean, I know we had already expanded the number of sites previously to get to a number that would support the full study, right, Baisong? And so, that was a very thoughtful approach to ensure that we had a good strong number of sites with geographic coverage.

Yes. Maybe I can add on Gena, we already shared, we have activated over 20 sites. And so, we are -- with that over 20 sites, we already enrolled 40 patients. And we already -- those sites for adolescent cohort that you have seen overlap between the adult and adolescent from the same study size, and we are also activating a few more sites that's specifically for a pediatric patient.

Our next question comes from Dae Gon Ha with Stifel.

I apologize, it's actually a 2-part question. But just to clarify, on the Reni-cel progress in RUBY. If I heard you correct, 18 dosed. I thought the prior conversation was 20 dosed by January. So, can you talk about sort of the dropouts there? What was the reason behind that?And then another clarification on the FDA side. When you talk about differentiation, have you guys actually engaged them on the angle you're taking on the differentiation, whether total hemoglobin or end organ function? How are they perceiving that in terms of the conversation?

Thanks very much, Dae Gon. First of all, I think we're actually very happy with where we are with our dosing, 18 patients dosed. And that really has us on track with that dosing pace to get us on track for a presentation of a substantial data set in the middle of the year, and actually, with regard to our driving towards BLA. We have not had dropouts. So I just want to be sure that there's no confusion about that.And I think the final thing is that Baisong and myself, with our clinical development experience, and particularly when you're dealing with a complex therapeutics like that, you're going to get some waves, ups and downs and waves of not just enrollment, but dosing, particularly around scheduling, around holiday periods, et cetera. So, as Baisong also said, we have many more patients scheduled for dosing in the coming months, and as I say, remain on track for a substantive data set in the middle of the year.With regard to differentiation and our conversations with the FDA, we have actually highlighted our potential differentiation, the mechanistic differences behind that et cetera. But I think it's too soon to comment on where the FDA and where our discussions with the FDA are on that.

Our next question is from Debjit Chattopadhyay with Guggenheim.

This is Ry Forseth from Debjit's team. Did the alignment with the FDA include any feedback on off target editing profiling akin to sort of the AdCom's criticism around CASGEVY's characterization for the breadth of genetic diversity. And our second question, for the yet-to-be-disclosed program where you're going to offer primate proof-of-concept, what characteristics of this program are you most excited about? The market size, the opportunity for first-in-class, the specific editing, chemistry, et cetera.

Thanks very much, Debjit. So let me actually pass the first question to Baisong.

Yes. We have continuous engagement with FDA. So, we are looking -- the engagement is scientific driven, is to understand the science of our molecule, the data we have and then how the patient was managed. And we are -- have a whole range of engagement with FDA from preclinical CMC to clinical. So, because -- as Gilmore mentioned, we have [Indiscernible] and we have a lot of leverage and a lot of opportunity to actually engage with FDA. So we are very happy with the collaborative nature of the FDA engagement.

And I kind of just add to that is that, as we said before, when we actually watched the AdCom discussion, we were very gratified by what we heard and saw, because our confidence both in the comprehensive nature of our off-target editing, oversight package was actually very robust relative to the discussion of the AdCom. And frankly, our off-target editing data package is actually very good, and not surprisingly, because we are using our own engineered AsCas12a enzyme, which is a high fidelity as well as high-efficiency enzyme. And it's worth saying that in our hands and in the hands of others, off-target editing is not detectable across a genome-wide screen as opposed to Cas9. So we feel very good about that.And then with regard to the in vivo characteristics, I think I just want to say, as I said before, that the key things or factors that we are focusing on is to select a set of targets that are high conviction, based on their potential for critical differentiation from the current standard of care. And it actually are -- it does include a number of variables, including the probability of technical success as well as regulatory success and commercial success.

Our next question comes from Phil Nadeau with TD Cowen.

Our question in on manufacturing. Can you remind us where you are in the scale process, the commercial manufacturing scale process? And in your discussions with the FDA, have you agreed upon a CMC package? And in particular, is there a requirement for patients in RUBY to be dosed with the commercial material?

Thanks very much for your question. From a CMC point of view, we actually are in a very good place. We have, as you know, had discussions with the FDA and are actually progressing very well along that line. We actually are -- as you know, we have -- are building our commercial capacity. And obviously, that capacity will be ready for the demand that will exist at the time of our launch and is ready for supporting demand beyond that launch.And then with regard to the processes, I'd say we're making excellent progress there in support of our BLA so that we would be BLA-ready and inspection ready at that time.

Our next question comes from Jay Olson with Oppenheimer & Co.

Congrats on all the progress. Our question is about your in vivo program. Can you talk about how and when you're planning to share preclinical proof of concept? And since it seems like there's 2 undisclosed targets in your corporate deck, are you planning to share preclinical proof of concept for both programs? And also, any thoughts you could share on your choice for editing tool and delivery tool?

Thanks very much. So, from the in vivo pipeline point of view, with regard to the how and the when, we're excited to be on track towards POC this year for an in vivo preclinical POC. And we're going to be able to share more and look forward to sharing more later in the year about the forum and the timing, whether it'd be a scientific forum or other forum in which we would share the data. And we haven't made a determination yet about that. And as I say, our focus is on driving towards a POC for in vivo this year.Oh, sorry, with regards to the editing tools, well, we have, I think, been very clear that we are focusing on our AsCas12a editor, and we are really focused on that we call for a number of reasons. First, it's our proprietary enzyme that we have selected going forward because of its high fidelity and high efficiency because of the benefits of it using a smaller guide and the advantages for quality, et cetera, in the manufacturing.And then finally, because we have human proof of concept. We have very exciting, robust editing data in human cells from AsCas12a from our Reni-cel program. So, all of those are the reasons why we're favoring and using that editing tool. And then with regards to delivery, we are using a non-viral -- focusing on non-viral delivery and nanoparticles, specifically.

Our next question comes from Yanan Zhu with Wells Fargo.

Great. We're just wondering about the mid-year readout from the RUBY trial. I think you have 18 patients dosed to-date. Are you going to report data on these 18 patients, plus any additional patient dosed with a certain amount of follow-up at the time of readout? And also, seems like this is a much bigger number compared with the last readout. So I was just wondering your confidence level of continuing to show the total hemoglobin normalization kind of the goal in this media readout?

Thank you, Yanan. Before passing to Baisong on some of the details, I agree with you. Yes, this is a much bigger number of patients that we have dosed, and our confidence, as we've said, has increased with the accumulation of data that are continuing and repeatedly show that not only are we achieving robust fetal hemoglobin expression in excess of 40%, which is well above the 30% threshold that natural history would tell us is relevant, but we actually also see that consistent correction of anemia to a normal physiological range in all men and all women treated and followed past 4 months to-date. And yes, we're excited about the mid-year disclosure. But with that, I'm going to pass it to Baisong to give you a little more detail.

Yes. Thanks Yanan. I mean, your understanding is absolutely correct. We already dosed 18 patients and we'll continue to do those patients in the coming months. So, the data set will be 18 patients and plus more that we're going to be dosing before the mid-year. And as you can see, we published data in ASH and some patients already over a year, then this patient will have continue to be monitor for those patients longer follow-up period. And then we have 18 patients dose now, and by the middle of the year and this will help, these patient -- these 18 patients we have 3 or 5 months more data by the time we release that. That's why we describe it as really very meaningful substantive data we will be able to share in the middle of year. As exactly you mentioned, we feel this data set is pretty strong.

Yes. And we actually, I think, Baisong, I think you said it, but it's worth reemphasizing, we're talking about ranges of follow-ups from an efficacy point of view between 3 and 18-plus months. So when you talk about the total [ core of ] patients now, we are now really building not just a data set that is robust in number, but actually as robust in follow-up period time, which is obviously relevant not just to our hematological and efficacy outcomes, but actually also increasing our confidence in durability.

Great, thanks. Looking forward to that.

Our next question comes from Luca Issi with RBC Capital.

Congrats on all the progress. Maybe Baisong any update on the Grade II polycythemia case that was potentially related to Reni-cel? I remembered the poster ASH actually noted the causality of the AEs was being investigated pending additional lab tests. So, just wondering if you have any update on that one? And then maybe just quickly, any update on partnering sickle-cell disease ex-U.S.?

So Baisong will take that first question. And with regard to partnering, I will just say that we are keen that a partner with a global footprint could help us with a global commercialization and development. We see that as an upside. But right now, our focus is on driving our sickle cell and thalassemia programs here in North America. And as I say, partnering will be something that we will look to in the future as upside.With regard to the erythrocytosis, Baisong?

Yes. Thanks. That specific patient will have a transient elevation of total hemoglobin as we report in ASH. At the time of ASH reporting, it's already been normal for more than 6 months. And that continues -- the patient's hematological parameter, including total hemoglobin continues to stay normal. And then the investigator has a further investigation of the patient's data, and we review that too, and the investigator consider this event is not related to the sickle -- Reni-cel treatment.

Our next question comes from Steve Seedhouse with Raymond James.

Hi, this is Timur Ivannikov for Steve Seedhouse. So we just had a clarification question on your PRO tools in RUBY. To what extent are you going to be using the same tools that Vertex and CRISPR used before, like EQ VAS, [ FACT-G ] and BMT? And to what extent do you think of including new tools on the issue being you're not going to be able to do a clean cross-trial comparison potentially here?

Yes. Thank you for the question. As I mentioned in a comment earlier, we use the tool from 2 ends. When it is more general, the quality of life tool as well as the sickle cell specific. And as you mentioned, the specific of the tool we're using, we have a domain for check the -- evaluate the fatigue of the patient, which is important not [ complaint ] from the sickle cell patient. Just give you example wise. And you are very much -- that is exactly the direction we were thinking, trying to see, okay, what are the specific instruments be able to detect that major complaint from the sickle cell patient, such as fatigue, such as pain, among other things.

Yes. So we are actually using a number of instruments. Some were used by Vertex, and we have additional instruments in our PRO armamentarium and they are actually being collected in the RUBY Phase I/II/III trial as we speak.

Our next question comes from Jack Allen with Baird.

Congratulations on the progress. I wanted to touch a little bit on the patient experience with Reni-cel. Have you provided any disclosures around the number of apheresis cycles that are required to receive Reni-cel, and I was wondering if the higher editing efficiency of Cas12a allows for a shorter amount of apheresis cycles. And then on the back end, after treatment, what are you seeing as it relates to time to neutrophil engraftment? And how do you think that compares to some of the competing products in the space?

Thanks very much, Jack. I'm actually going to ask Baisong to talk about the clinical experience with apheresis and other elements of the patient experience and obviously touch on neutrophil engraftment, with which we have been very pleased to date.

Thank you, Jack. For patient experience, I mean apheresis is definitely a very important part of that. As I mentioned earlier, since I joined, I worked with the team and experts, we managed the protocol and trying to optimize the apheresis process. So now we are very happy with the number of cycles that the patient has been going through, and we can see that's already improvement from what we had before.In terms of the engraftment, as we disclosed in ASH, we have, all the patients who have engraftment, it's under -- within 30 days. So we're very happy about that. And we continue to see the similar data as we follow through the protocol for follow-on studies.

We have reached the end of our question-and-answer session. This concludes today's conference. Thank you for your participation. You may disconnect your lines at this time.